HAEM5:Acute myeloid leukaemia with CEBPA mutation

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Acute Myeloid Leukemia (AML) with Biallelic Mutations of CEBPA.

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Xinxiu Xu, Vanderbilt University Medical Center

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Acute myeloid leukaemia
Type	Acute myeloid leukaemia with defining genetic abnormalities
Subtype(s)	Acute myeloid leukaemia with CEBPA mutation

WHO Essential and Desirable Genetic Diagnostic Criteria

WHO Essential Criteria (Genetics)*	>= 20% blasts with a myeloid immunophenotype in the bone marrow or blood; presence of biallelic mutations in CEBPA, or a single mutation located in the bZIP region; absence of criteria allowing for classification into other AMLs with defining genetic abnormalities; not fulling diagnostic criteria for myeloid neoplasm post cytotoxic therapy.
WHO Desirable Criteria (Genetics)*	NA
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

Acceptable	acute myeloid leukaemia with biallelic mutation of CEBPA.
Not Recommended

Gene Rearrangements

None.

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: ABL1	EXAMPLE: BCR::ABL1	EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.	EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: Common (CML)	EXAMPLE: D, P, T	EXAMPLE: Yes (WHO, NCCN)	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
EXAMPLE: CIC	EXAMPLE: CIC::DUX4	EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5.	EXAMPLE: t(4;19)(q25;q13)	EXAMPLE: Common (CIC-rearranged sarcoma)	EXAMPLE: D		EXAMPLE: DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).

Individual Region Genomic Gain/Loss/LOH

None.

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

Characteristic Chromosomal or Other Global Mutational Patterns

None.

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

Gene Mutations (SNV/INDEL)

Patients with biallelic CEBPA mutations and a normal karyotype have a more favorable prognosis than those with monoallelic or no CEBPA mutations, with higher complete remission rates and longer disease-free survival, relapse-free survival, event-free survival, and overall survival. Patients with abnormal karyotypes (but not complex karyotypes) and biallelic CEBPA mutations also have longer disease-free survival, event-free survival, and overall survival when compared to patients with monoallelic or no CEBPA mutations. Detection of biCEBPA should raise possibility of germline mutation. Approximately 5-10% of biCEBPA AML cases have a germline N-terminal. In the familia from, AML has very high penetrance and presents relatively early (median aga: 245.5 years). There are some notable familial AML-Associated CEBPA germline pathogenic variants: c.68delC, p.Pro23ArgfsTer137; c.68dupC, p.His24AlafsTer84; c.141delC, p.Ala48ProfsTer112; c.147_165del19, p.Glu50AlafsTer104; c.158delG, p.Gly53AlafsTer107; c.189delC, p.Asp63GlufsTer97; c.314_315insT, p.Phe106LeufsTer2; c.932A>C, p.Gln311Pro; c.442G>T, p.Glu148Ter.

Pathogenic mutations in CEBPA are predominantly insertion/deletion frameshift mutations in the N-terminal TAD region and in-frame C-terminal bZIP mutations. Patients with biCEBPA and smbZIP-CEBPA are younger and have higher white blood cell counts than those with a single mutation in the N-terminal TAD region. No particular mutational hotspots exist but the following table records the most reported mutations in the COSMIC database (frequency based on a count out of 1523 mutations):

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
CEBPA	c.939_940insAAG, p.K313_V314insK	Oncogene	Recurrent (AML)	D, P, T	Yes (NCCN)	AML with CEBPA mutation is associated with favorable prognosis. AML with CEBPA mutation constitutes ~5% pf pediatric AML and 5-11% adult AML.
CEBPA	c.68_69insC, p.H24fs*84	Oncogene	Recurrent (AML)	D, P, T	Yes (NCCN)
CEBPA	c.247delC, p.Q83fs*77	Oncogene	Recurrent (AML)	D, P, T	Yes (NCCN)
CEBPA	c.936_937insCAG, p.Q312_K313insQ	Oncogene	Recurrent (AML)	D, P, T	Yes (NCCN)
CEBPA	c.912_913insTTG, p.K304_Q305insL	Oncogene	Recurrent (AML)	D, P, T	Yes (NCCN)
		Oncogene	Recurrent (AML)	D, P, T	Yes (NCCN)
		Oncogene	Recurrent (AML)	D, P, T	Yes (NCCN)

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

The content below was from the old template. Please incorporate above.

Pathogenic mutations in CEBPA are predominantly insertion/deletion frameshift mutations in the N-terminal TAD region and in-frame C-terminal bZIP mutations. No particular mutational hotspots exist but the following table records the most reported mutations in the COSMIC database (frequency based on a count out of 1523 mutations):

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
CEBPA	c.939_940insAAG, p.K313_V314insK	Oncogene	LOF	52
CEBPA	c.68_69insC, p.H24fs*84	Oncogene	LOF	43
CEBPA	c.247delC, p.Q83fs*77	Oncogene	LOF	32
CEBPA	c.936_937insCAG, p.Q312_K313insQ	Oncogene	LOF	28
CEBPA	c.912_913insTTG, p.K304_Q305insL	Oncogene	LOF	24

Other Mutations

Concurrent mutations in NPM1 and FLT3 are seen less frequently in individuals with biallelic CEBPA mutations than in those with no or monoallelic mutations. Conversely, mutations in GATA2 appear to occur more often in CEBPA single- and double-mutants. The prognostic significance of these concomitant mutations is, however, unclear. Biallelic CEBPA mutations appear to confer a positive prognostic effect regardless of concomitant mutations.

Type	Gene/Region/Other
Concomitant Mutations	NPM1, FLT3, GATA2
Secondary Mutations	None
Mutually Exclusive	None

End of V4 Section

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Epigenomic Alterations

None

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

editv4:Genes and Main Pathways Involved

The content below was from the old template. Please incorporate above.

CEBPA, located on chromosome 19 band q13.1, encodes a transcription factor of the basic region leucine zipper (bZIP) family. It is involved in the coordination of myeloid differentiation and cellular growth arrest. Alternative translation initiation sites result in protein isoforms of different lengths.

CEPBA works in a tissue-specific manner to direct cellular differentiation by activating lineage-specific gene promoters. Interactions with the basal transcriptional apparatus (TBP/TFIIB), histone acetylators (CBP/p300), and chromatin-remodelling complexes (SWI/SNF) have all been implicated in lineage-specific gene activation by CEBPA. In the haematopoietic system there appears to be interplay between CEBPA and GATA factors. CEBPA knockout mice show a complete lack of granulocytes while blasts accumulate in the bone marrow, suggesting an early block of myeloid maturation. In the context of haematopoietic differentiation, evidence suggests CEBPA plays a role in regulating the expression of genes encoding growth factor receptors (e.g. granulocyte colony-stimulating factor) and secondary granule proteins (e.g. lactoferrin). It has also been implicated, along with NFI-A, in mediating miR-223 expression. Studies indicate that CEBPA is not required for differentiation of granulocytes beyond the granulocyte-monocyte progenitor (GMP) stage, and that CEBPA controls stem-cell renewal with expression of Bmi-1 elevated in 'CEBPA knockouts. Proliferation arrest also appears to be an important aspect of CEBPA function via interaction with CDK2/CDK4, upregulation of the p21 (WAF-1/CIP-1/SDI-1) protein and the SWI/SNF complex, and inhibition of the E2F complex. This E2F inhibition leads to c-myc downregulation, which is required for granulocytic regulation. Mutations in the C-terminal region of CEBPA abrogate CEBPA-E2F complex function. The precise mechanism by which CEBPA mutants inhibit granulocytic differentiation in the context of AML is still unclear.

End of V4 Section

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Genetic Diagnostic Testing Methods

Sanger sequencing, Next Generation Sequencing

Familial Forms

Familial mutations of CEBPA have been described in several families. Typically, these are N-terminal mutations that are later joined by a somatic C-terminal mutation on the opposite allele leading to AML.

Additional Information

Put your text here

Links

CEBPA

References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):

Paul Defazio, MSc, Monash Health

*Citation of this Page: “Acute myeloid leukaemia with CEBPA mutation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 05/17/2025, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_CEBPA_mutation.